Synthesis and structure–activity analysis of new phosphonium salts with potent activity against African Trypanosomes

Taladriz, A. et al. (2012) Synthesis and structure–activity analysis of new phosphonium salts with potent activity against African Trypanosomes. Journal of Medicinal Chemistry, 55(6), pp. 2606-2622. (doi: 10.1021/jm2014259)

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A series of 73 bisphosphonium salts and 10 monophosphonium salt derivatives were synthesized and tested in vitro against several wild type and resistant lines of Trypanosoma brucei (T. b. rhodesiense STIB900, T. b. brucei strain 427, TbAT1-KO, and TbB48). More than half of the compounds tested showed a submicromolar EC50 against these parasites. The compounds did not display any cross-resistance to existing diamidine therapies, such as pentamidine. In most cases, the compounds displayed a good selectivity index versus human cell lines. None of the known T. b. brucei drug transporters were required for trypanocidal activity, although some of the bisphosphonium compounds inhibited the low affinity pentamidine transporter. It was found that phosphonium drugs act slowly to clear a trypanosome population but that only a short exposure time is needed for irreversible damage to the cells. A comparative molecular field analysis model (CoMFA) was generated to gain insights into the SAR of this class of compounds, identifying key features for trypanocidal activity.

Item Type:Articles
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry
Authors: Taladriz, A., Healy, A., Flores Pérez, E.J., Herrero García, V., Ríos Martínez, C., Alkhaldi, A.A.M., Eze, A.A., Kaiser, M., De Koning, H.P., Chana, A., and Dardonville, C.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Journal of Medicinal Chemistry
Published Online:06 March 2012

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
496491Uptake of novel diamidine drugs by Trypanosoma bruceiHarry De KoningRoyal Society (ROYSOC)JP0872898Infection Immunity and Inflammation Life Sciences